Benzonorbornene derivatives, processes for their preparation and medicinal and cosmetic compositions containing them

ABSTRACT

A compound of formula (I) ##STR1## its isomers and its salts in which --R 1 , R 3  and R 4  are each independently hydrogen, C 1  -C 8  -alkyl, C 1  -C 8  -alkoxy, halogen, C 1  -C 8  -acyloxy or hydroxyl; 
     --R&#39; is hydrogen or C 1  -C 6  -alkyl; 
     --R&#34; is either a polyene chain or a benzene ring are useful in cosmetics and in the treatment of various dermatological and other complaints.

This is a continuation of application Ser. No. 07/218,204, filed July13, 1988, now U.S. Pat. No. 4,931,589, which is a continuation of Ser.No. 06/772,525, filed Sep. 4, 1985, now U.S. Pat. No. 4,783,549.

DESCRIPTION

The invention relates to benzonorbornenes substituted on the benzenering, and to a process for preparing them. The invention also relates tothe use of these new compounds, either in cosmetic compositions or inpharmaceutical compositions for the treatment of dermatologicalcomplaints related to a keratinization (differentiation-proliferation)disorder, for the treatment of dermatological or other complaints withan inflammatory and/or immuno-allergic component, in the treatment ofthe diseases of degeneration of the conjunctive tissue and of tumors,and in the treatment of rheumatoid psoriasis. Furthermore thesecompounds may be used in opthalomology, particularly in the treatment ofcorneopathies.

The therapeutic action of vitamin A in its acid, aldehyde or alcoholform is well known in dermatology (see, on this subject, the publication"Experientia", volume 34, pages 1105-1119 (1978)); this action in thetreatment of cutaneous proliferations, of acne, of psoriasis and ofsimilar complaints will be referred to hereafter by the generalexpression "retinoid-type action".

It has been found that products with a structure similar to that ofvitamin A also have a retinoid type action, but that the secondaryeffect of toxic hypervitaminosis could, in the case of some compounds,be multiplied by a lower factor than the multiplication factor of therequired retinoic effect (see, on this subject, Eur. J. Med.Chem.-Chimica Therapeutica, January-February 1980, 15, No. 1, pages9-15); thus, French Patent Applications 2,422,620 and 2,529,458 describenew stilbene and methylstyrylnaphthalene derivatives incorporating, onthe ring on which an unsaturated substituted chain is grafted, a numberof methyl groups, because the studies carried out led to the conclusionthat multiplication of the methyl groups appeared to improve thetherapeutic effectiveness (see the above-mentioned publication Eur. J.Med. Chem.).

Benzonorbornene and some of its derivatives were already known (see, onthis subject, J. Org. Chem., 32, pages 893-901 (1967) and J. Am. Chem.Soc., 87, 21, pages 4794-4804 (1965)), but it had never beendemonstrated that these benzonorbornene derivatives could have aretinoic action. Subsequently, it has been shown that some norbornenederivatives have a retinoic activity (see, on this subject, thepublication J. Med. Chem. 1980, 23, pages 1013-1022 and 1981, 24, pages1214-1223). However, in endeavoring to improve therapeuticeffectiveness, the person skilled in the art, knowing that it wasnecessary to increase the methyl substitutions on this ring, tended tomove away from benzonorbornene derivatives. Now, it has been found,according to the invention, that, surprisingly singly, somebenzonorbornene derivatives have a particularly advantageousretinoid-type action.

The present invention provides a benzonorbornene derivative of formula(I) or an isomer or salt thereof, wherein formula (I) is ##STR2## inwhich: --R₁, R₃ and R₄ are each independently hydrogen, C₁ -C₈ alkyl, C₁-C₈ alkoxy, halogen, C₁ -C₈ acyloxy or hydroxyl;

--R' is hydrogen or C₁ -C₆ alkyl; --R" is an unsaturated group which is:

either 1) a polyene chain of formula (II) ##STR3## in which A₂ is eithera group CH₂ OR₆ in which R₆ is hydrogen or C₁ -C₆ alkyl or a group COR₇in which R₇ is hydrogen, C₁ -C₆ alkoxy, aryloxy, benzyloxy, a sugarresidue, substituted or unsubstituted amino, C₁ -C₆ alkyl or hydroxyl;

or 2) a benzene ring of formula (III) ##STR4## in which A₃ may be any ofthe meanings given earlier for A₂ or may be hydrogen, C₁ -C₆ alkyl,alkylthio(--SR5), alkylsulphinyl ##STR5## or alkylsulphony (--SO₂ R₅),wherein R₅ is C₁ -C₆ alkyl;

provided that if R' is H or methyl, R₁ ═R₄ ═H and R3 is H or methyl, R"cannot be a group of formula (III) in which A₃ is --COR₇ in which R₇ isOH, alkoxy, aryloxy or --NR₁₀ R₁₁ where R₁₀ is a linear or branchedalkyl, substituted or unsubstituted by OH, and R₁₁ is H or a linear orbranched alkyl, substituted or unsubstituted by OH.

When the substituent A₂ or A₃ denotes a group COR₇ and R₇ is a C₁ -C₆alkoxy radical, it is preferred that R₇ be a radical OR₈, R₈ beingchosen from the group formed by the methyl, ethyl, propyl, isopropyl,butyl, t-butyl and hexyl radicals and by C₁ -C₆ alkyl radicalssubstituted by one or more hydroxyls, such as 2-hydroxyethyl,2-hydroxypropyl or the isomers of dihydroxypropyl such as2,3-dihydroxypropyl, 1,3-dihydroxy-2-propyl, or pentaerythritol.

When the substituent A₂ or A₃ denotes a group COR₇ and R₇ is a hydroxyl,this carboxylic group can advantageously be converted to a salt. Theinvention also relates to salts of compounds of formula (I) e.g. thoseof zinc, alkalineearth metal, alkali metal or an organic amine such astriethanolamine.

When the substituent A₂ or A₃ is a group COR₇ and R₇ is an aryloxygroup, the aryl radical of R₇ can advantageously correspond to theformula (IV): ##STR6## in which R₉ and R₁₃ are each independentlyhydrogen, C₁ -C₄ alkyl, hydroxyl, halogen, a trifluoromethyl or alkoxygroup.

When the substituent A₂ or A₃ is a group COR₇ and R₇ is a benzyloxygroup, the benzyl radical of R₇ can advantageously correspond to theformula (V): ##STR7## in which R₉ and R₁₃ have the same meanings as inthe formula (IV).

When the substituent A₂ or A₃ is a group COR₇ and R₇ is a sugar residue,COR₇ advantageously originates from a glucose ester or a mannitol ester.

When A₂ or A₃ is COR₇ and R₇ is an amino of formula NR₁₀ R₁₁, R₁₀ andR₁₁ are each independently, preferably, hydrogen, C₁ -C₆ alkyl which isstraight-chain or branched and which is substituted or unsubstituted byone or more hydroxyls, or, R₁₀ and R₁₁ taken together with the N atom towhich they are attached, form a substituted or unsubstitutedheterocyclic ring, one of R₁₀ or R₁₁ also being capable, when the otheris hydrogen, of being aryl of formula (IV) or benzyl of formula (V),formulae in which R₉ and R₁₃ have the meanings given above. NR₁₀ R₁₁ canalso correspond to the amine function of an aminoacid or to the aminefunction of the glucosamine.

When R" is a polyene chain of formula (I), if the carbon bearing thesubstituent A₂ is given the number 2, the carbon bearing the methylsubstituent the number 3 and the subsequent carbon adjacent to thelatter in the chain the number 4, the structures at carbons 2 and 4 maybe 2-E, 4-E or 2-Z, 4-Z or 2-E, 4-Z or 2-Z, 4-E. In general, thecompounds of formula (I) according to the invention may be of transstructure (structure E) or of cis structure (structure Z); the inventioncovers all the isomers as well as the optical isomers. Furthermore, ithas to be stated that when these products are exposed to light,conversion from one type of isomer to another type may take place.

Preferred compounds of the invention are those of formula (I') ##STR8##in which R₁, R₃ and R₄ are as defined above, R' is hydrogen or methyl,R" is a chain of formula (II) in which A₂ is --COR₇ in which R₇ ishydroxy, C₁ -C₆ alkoxy or amino; and isomers and acid salts thereof.

The invention also relates to two processes for preparing the newcompounds of formula (I) and their isomers and salts. In all cases,these preparation processes employ, as a starting compound, a2-acylbenzonorbornene of formula ##STR9##

The invention also provides a compound corresponding to theabove-mentioned formula (VII), in which R₁, R₃, R₄ and R' have themeanings given earlier, but R' may not be H or methyl when R₁ ═R₄ ═H andR₃ is H or methyl.

This compound of formula (VII) may be obtained in various ways,depending on the nature of the substituents, as will be indicated later.

According to a first process, the compound of formula (VII) is reacteddirectly with a dialkyl phosphonate of formula: ##STR10## in which 12 isC₁ -C₆ alkyl or with a triphenylphosphonium salt of formula (IX):

    (C.sub.6 H.sub.5).sub.3 P.sup.⊕ --CH.sub.2 --R" X.sup.⊖(IX)

R" having, in these two formulae, the meanings given earlier, X.sup.⊖denoting a halide. The product may be isomerized or salified ifnecessary.

According to a second process the compound of formula (VII) is obtainedina first step and, ina second step, it is reduced with sodiumborohydride to a secondary alcohol of formula: ##STR11## in a third stepthe compound of formula (X) is converted by the action of phosphorustribromide to a bromide of formula: ##STR12## in a fourth step, thecompound of formula (XI) is treated with triphenylphosphine to obtainthe triphenylphosphonium bromide of formula: ##STR13## in a fifth stepthe compound of formula (XII) is reacted with an aldehyde R"--CHO toobtain the compound of formula (I), R', R", R₁, R₃ and R₄ having inthese formulae the meanings given earlier. The product may then beisomerized or salified if necessary.

Among the aldehydes which may be employed, mention may be made of methyl4-formylbenzoate, which is available commercially.

As an example of an aldehyde, use has also been made of ethyl5-formyl-3-methyl-2,4-pentadienoate, which is synthesised in two steps,as indicated in the abovementioned publication "Experientia" 1978, 34,pages 1105-1119 (see also Chemical Abstracts 57, 2056 b and 58, 10066e); in this process, pyruvic aldehyde dimethyl acetal and triethylphosphonoacetate, which are both commercial products, are reacted in thepresence of sodium hydride in tetrahydrofuran. This produces anunsaturated ester, which is condensed with ethyl vinyl ether in thepresence of boron trifluoride etherate; the condensation product is thenhydrolyzed with phosphoric acid and the aldehyde obtained is purified byrecrystallization.

It should be noted that the two access routes to the product of formula(I) which form the two preparative processes mentioned above are notequivalent and need to be chosen as a function of the nature of thesubstituents.

To obtain the compounds of formula (VII) which serve as startingmaterial in the two preparative processes it is possible in a firstalternative form to prepare, in a first step, a benzonorbornene offormula (VI): ##STR14## formula in which R₁, R₃ and R₄ have the meaningsgiven earlier; in a second step, the compound of formula (VI) isacylated with an acyl chloride R'COCl, in the presence of aluminiumchloride, to obtain the 2-acylbenzonorbornene of formula (VII), R'having the meanings given earlier.

According to another alternative form, in a first step, the acylation iscarried out with an acyl chloride or an acid anhydride giving rise tothe appearance of the group R'--CO-- on the benzonorbornene ring, andthen, in a second step, the substituents R₁, R₃ and R₄ are attached tothe compound obtained, R', R₁, R₃ and R₄ having the meanings givenearlier.

The choice between the two abovementioned alternative ways of producingthe compound of formula (VII) is made according to the nature of thesubstituents.

According to a third alternative form, which can also be employed whenthe nature of the substituents allows this, the compound of formula(VII) is obtained by carrying out, in a first step, the cycloaddition ofa benzyne of formula (XXV): ##STR15## with cyclopentadiene, R₃ havingthe meanings given earlier; in a second step, the benzonorbornadiene offormula (XXIII): ##STR16## thus obtained is reduced to a benzonorborneneof formula (XXIV): in a third step, the compound of formula (XXIV) isacylated with an acyl chloride (R'COCl), in the presence of aluminumchloride, to produce the compound of formula (VII) R' having themeanings given earlier.

By way of nonrestrictive examples of the preparative methods definedabove, the access routes corresponding to some compounds of formula(VII) will be given more precisely below.

FIRST EXAMPLE OF ACCESS TO THE COMPOUNDS OF FORMULA (VII)

Synthesis of the compounds of formula (VII) in which R₁ ═R₄ ═H; R₃ ═C₁-C₈ alkyl; and R' ═C₁ -C₆ alkyl.

As a starting material, use is made of unsubstituted2-acylbenzonorbornenes of formula (XIV): ##STR17## formula in which R'"is defined by the fact that R₃ ═R'"--CH₂. 2-Acylbenzonorbornenes offormula (XIV) in particular are obtained by the following operatingprocedure:

a) to obtain benzonorbornadiene of formula (i) ##STR18## freshlydistilled cyclopentadiene is reacted with benzyne of formula (ii)##STR19##

Benzyne of formula (ii) is prepared either from 2-aminobenzoic acid offormula (iii) ##STR20## which is treated with isoamyl nitrite, or fromthe organomagnesium derivative of 2-bromofluorobenzene of formula (iv)##STR21##

b) benzonorbornadiene of formula (i) is purified by distillation andthen reduced by hydrogenation in the presence of palladium on charcoal,the reduction making it possible to obtain benzonorbornene of formula(v) ##STR22##

c) benzonorbornene of formula (v) is acylated by a Friedel-Craftsreaction with acyl chloride in the presence of aluminum chloride; thisacylation is selective for β and the required 2-acylbenzonorbornene offormula (XIV) ##STR23## is obtained, which serves as a starting materialin the preparative process according to the invention.

The compound of formula (XIV) is subjected to a Wolff-Kishner reductionto obtain 2-alkylbenzonorbornene of formula (XV): ##STR24##

The compound of formula (XV) is then acylated by a Friedel-Craftsreaction with an acyl chloride R'COCl, in the presence of aluminumchloride, to obtain the 2-acyl-3-alkylbenzonorbornene of formula (XVI):##STR25##

SECOND EXAMPLE OF ACCESS TO THE COMPOUNDS OF FORMULA (VII)

Synthesis of the compounds of formula (VII) in which R₁ and/or R₄ ═Br;R₃ ═C₁ -C₈ alkyl or H; and R'═C₁ -C₆ alkyl.

Use is made of the compounds 9f formulae (XVI) or (XIV) preparedbeforehand, and they are treated directly with one or two equivalents ofbromine in the presence of aluminum bromide; the mono- or dibrominated2-acylbenzonorbornene, optionally alkylated in the 3 position, offormula (XVII): ##STR26## is thus obtained.

THIRD EXAMPLE OF ACCESS TO THE COMPOUNDS OF FORMULA (VII)

Synthesis of the compounds of formula (VII) in which R₁ ═R₄ ═C₁ -C₈alkoxy and R₃ ═H or C₁ -C₈ alkyl. Use is made, as a starting material,of 1,4-dihydroxybenzonorbornene of formula (XIX): ##STR27## Thiscommercial product is subjected, in a basic medium, to an alkylationwith an alkyl halide R'"X, where X is a halogen atom and R'"is definedby the fact that R₁ ═R₄ ═OR'". In this way a 1,4-dialkoxybenzonorborneneof formula (XX): ##STR28## is obtained.

The compound of formula (XX) is then acylated with an acyl chlorideR'COCl in the presence of aluminum chloride to obtain a2-acyl-1,4-dialkoxybenzonorbornene of formula (XVIII) ##STR29## formulawhere R' has the meanings given for the formula (I)

By way of additional information it may be mentioned that the compoundof formula (XVIII) may be employed to obtain compounds of formula (I) bybeing condensed directly with compounds of formula (VIII) or (IX), thatis to say by making use of the first preparative process.

FOURTH EXAMPLE OF ACCESS TO THE COMPOUNDS OF FORMULA (VII):

Synthesis of the compounds of formula (VII) in which R₁ ═R₄ ═C₁ -C₈alkoxy and R₃ ═C₁ -C₈ alkyl.

The compound of formula (XVIII) is used as a starting material. The acylgroup of the compound of formula (XVIII) is reduced to a correspondingalkyl group to obtain the compound of formula (XXVI): ##STR30##

The trisubstituted benzonorbornene of formula (XXVI) is acylated with anacyl chloride R'COCl, in the presence of aluminum chloride, to obtain a2-acyl-3-alkyl-1,4-dialkoxybenzonorbornene of formula (VII), R' beingdefined by the fact that R₃ ═CH₂ R'.

It has been found that the compounds of formula (I) their isomers andtheir salts have a retinoid type action and are particularly suitablefor treating the dermatological complaints related to a keratinization(differentiationproliferation) disorder, and dermatological or othercomplaints with an inflammatory and/or immuno-allergic component,particularly for treating common, comedonian or polymorphous acnes,senile or solar acnes, medicamentous or occupational acnes, extensiveand/or severe forms of psoriasis and other keratinization disorders,particularly ichthyosis and ichthyosiform states, Darier's disease,palmo-plantar keratosis, leucoplasias and leucoplasiform states, lichenplanus, and all benign or malignant, severe or extensive dermatologicalproliferations; they are also active against rheumatoid psoriasis; theycan be advantageously used in dystrophic epidermolysis bullosa and inthe molecular pathology of collagen; they also find a use in UV inducedcarcinomas (solar carcinogens), in epidermodysplasia verruciformis andapparent epidermodysplasia. They further have an application inophthalmology and particularly in relation to corneopathies. As aresult, the invention also covers medicinal compositions containingthese compounds.

These compounds show good activity in the ornithine decarboxylase (ODC)inhibition test after induction by "tape stripping" in the hairless rat(Dermatologica 169, No. 4 (1984) "A Rapid and Simple Test System for theEvaluation of the Inhibitory Activity of Topical Retinoids on CellotapeStripping Induced ODC Activity in the Hairless Rat" M. Bouclier et al.).This test is recognised as a measurement of the action of retinoids onthe cellular proliferation phenomena.

The compounds also show activity in the differentiation test of cells ofembryonic terato-carcinomas of mice (cells Fg): "Cancer Research" 43, p.5268 (1983).

The compounds have an excellent comedolytic activity in the test on theRhino mouse described by Bonne et al. in the International Journal ofCosmetic Science 3, 23-28 (1981). This testing is carried out on theskin of the Hairless Rhino mouse, recommended by Van Scott in 1972 as amodel for screening comedolytic agents and based on the histologicalpicture.

The present invention consequently also relates to a compositionsuitable for pharmaceutical use, intended particularly for the treatmentof the above-mentioned complaints, which comprises, in apharmaceutically acceptable carrier, at least one compound of formula(I), and/or one of its isomers and/or one of its salts.

When these compounds are employed by topical administration it isobserved that they have a good activity over a very wide range ofdilution; in particular, use can be made of concentrations of activecompound(s) ranging from 0.0005% to 2% by weight. It is possible, ofcourse, to employ higher concentrations when this is required for aparticular therapeutic application; however, the preferredconcentrations of active principle are from 0.002 to 1% by weight.

The topical compositions are advantageously in the form of ointments,salves, tinctures, creams, emulsions, solutions, lotions, sprays,powders, gels, suspensions, patches or saturated pads. The compounds aremixed with inert, nontoxic, generally liquid or pasty bases which aresuitable for treatment by a topical route.

The compounds may be employed by an enteral route. By the oral route thecompounds are administered in a proportion of approximately 2 μg up to 2mg per day and per kg of the body weight; an excessive dosage may appearin the form of a hypervitaminosis A recognizable by its symptoms andcapable of suggesting a hepatic toxicity requiring a biological controlof the hepatic function. The required dosage may be administered as oneor more doses. For administration by the oral route, the suitable formsare, for example, tablets, gelatin capsules, coated tablets, syrups,suspensions, solutions, powders, granules or emulsions; a preferred modeof administration consists in using gelatin capsules containing from 0.1mg to approximately 1 mg of active substance(s).

The compounds may also be administered by parenteral route in the formof solutions or suspensions for perfusions or intravenous orintramuscular injections. In this case, the compounds are advantageouslyadministered in a proportion of approximately 2 μg up to 2 mg per dayand per kg of body weight; in general, parenteral administration iscarried out in a proportion of 0.01 mg to 1 mg of active substance(s)per ml.

When the compounds of the invention are administered by an ocular route,they are advantageously presented in the form of a solution or a powderto be diluted to give an eye lotion.

Depending on the forms employed, the pharmaceutically acceptable basecan contain, for example, water, gelatin, lactose, starch, talc,vaseline (liquid petrolatum), gum arabic, polyalkylene glycols, andmagnesium stearate. The tablets, powders, granules, coated tablets orgelatin capsules may contain binders, fillers or pulverulent bases; thesolutions, creams, suspensions, emulsions or syrups may containdiluents, solvents or thickeners.

The compounds of formula (I) their isomers and their salts, also find anapplication in the cosmetic field, in particular in body hygiene andhair care and, in particular, in the treatment of acne, seborrheas, forregrowth of hair, for combating hair loss, for combating the oilyappearance of the skin or hair, or for treating physiologically dryskins. They can also be used for curing and preventing the harmfuleffects of sunlight.

The present invention consequently also provides a cosmetic compositioncontaining, in a cosmetically acceptable carrier, at least one compoundof formula (I) one of its salts or isomers, this composition being inparticular in the form of a lotion, gel, cream, soap or shampoo.

The concentration of the compound(s) in these cosmetic compositions isgenerally from 0.0005% to 2% by weight and, preferably, from 0.01% to 1%by weight relative to the total weight of the composition.

In the treatment of the above-mentioned disorders, these compounds whichare employed in the compositions act by increasing the epithelialfollicular production of nonadhesive cells, thus displacing andexpelling the contents of the acne comedon. These compounds reduce thesize of the sebaceous glands and partially inhibit sebum secretion.

The compositions may contain inert or even pharmacodynamically orcosmetically active additives, and particularly:

hydrating agents such as thiamorpholinone and its derivatives, or urea;

antiseborrheic or antiacne agents, such as those described in FrenchPatents Nos. 1,472,021, 1,505,874, 1,560,250, 2,002,461, 2,035,799,2,011,940, 2,060,407, 2,126,996, 2,133,991, 2,133,992, 2,139,876,2,158,018, 2,296,406, 2,428,436, 2,468,362, 2,446,277, 2,447,187 andU.S. Pat. No. 2,332,418 and, in particular, S carboxymethylcysteine,S-benzylcysteamine, their salts and their derivatives, thioxolone, orbenzoyl peroxide;

antibiotics such as erythromycin and its esters, for example thosedescribed in U.S. Pat. No. 2,862,921 or French Patent Application85/05,785, neomycin, tetracyclines or4,5-polymethylene-3-isothiazolinones such as those described in FrenchPatent No. 2,492,376;

agents promoting the regrowth of hair, such as minoxidil(2,4-diamino-6-piperidinopyrimidine 3-oxide) and its derivatives,diazoxide (3-chloromethyl-1,2,4-benzothiadiazine-1,1-dioxide), phenytoin(5,5-diphenyl-2,4imidazolidinedione), oxypropanium iodide or anthralinand its derivatives;

antiinflammatory (steroid and non-steroid) agents;

carotenoids and, in particular, β-carotene;

antipsoriatic agents such as eicosa-5,8,11,14-tetraynoic and5,8,11-triynoic acids, their esters and their amides, anthralin and itsderivatives, such as those described in French Patents 2,113,952,2,492,372, 2,492,373, 2,495,934, 2,499,556, or French PatentApplications Nos. 84/09,203 and 84/10,324, or U.S. Pat. No. 4,299,846,naphthalene and naphthoquinone derivatives such as those described inU.S. Pat. No. 4,299,478, European Patent 7985 or in J.I.D. 84 (4) 358(1985).

The compositions can also contain flavoring agents, preserving agents,stabilizers, moisture-controlling agents, pH-controlling agents, agentsmodifying osmotic pressure, emulsifiers, UV-A and UV-B screens such asthose described in French Patents Nos. 1,179,387 or 2,528,420, andantioxidants such as α-tocopherol, butylated hydroxyanisole or butylatedhydroxytoluene.

The present invention will be further described by the followingExamples.

Examples a, b and c describe preparative steps preceding the steps whichare an integral part of the preparative process according to theinvention.

Examples A and D to H illustrate the preparation of a number ofcompounds of formula (VII).

Examples B and C illustrate the preparation of the precursors ofcompounds of formula (VII).

EXAMPLE a Preparation of 2-acetylbenzonorbornene (formula (XIV) withR'"═CH₃)

Fist step: preparation of benzonorbornadiene (formula (i))

10 g of magnesium turnings which are covered with approximately 75 cm³of anhydrous tetrahydrofuran are placed in a round flask fitted with acondenser, a thermometer, a nitrogen inlet, a dropping funnel, andprotected from atmospheric moisture by a calcium chloride tube. 25 cm³of a solution, prepared beforehand, of 65 g of ortho-fluorobromobenzeneand 26 g of cyclopentadiene in 200 cm³ of anhydrous tetrahydrofuran arethen added. The formation of the organomagnesium compound is initiatedby heating the reaction mixture locally with a hairdryer, and thesolvent is then kept at boiling point by dropwise addition of theremaining solution. The whole addition is completed in approximately 1hour. The mixture is then filtered at ambient temperature and thesolution is concentrated under reduced pressure. The solution is takenup again in ether and the ether phase is washed with ammonium chloride,separated by gravity and dried over magnesium sulphate; the solvent isthen removed by evaporation under vacuum. The residue is then distilledand benzonorbornadiene, whose boiling point is 82°-83° C. at a pressureof 16 millibars, is obtained in a yield of 40%.

Second step: preparation of benzonorbornene (formula V)

4 g of a catalyst containing 10% of palladium on charcoal are added to asolution of 40 g of benzonorbornadiene in 400 cm³ of nitrogen-degassedmethanol. Nitrogen is again bubbled into this mixture and theheterogeneous solution is stirred for three hours at a gauge pressure ofhydrogen of 2 bars. The mixture is then filtered, concentrated underreduced pressure and benzonorbornene is purified by distillation; itsboiling point at 22.5 millibars is 86° C. 33 g of a product whosenuclear magnetic resonance spectrum corresponds to the expectedstructure are obtained.

Third step: preparation of 2-acetylbenzonorbornene (formula XIV withR'"═CH₃)

30 cm³ of acetyl chloride are added to a solution of 30 g ofbenzonorbornene in 400 cm³ of carbon disulphide and then 10.5 g ofanhydrous aluminum chloride are added gradually in small quantities overapproximately 2 hours. At this stage, the complete conversion of thestarting product is checked by thin-layer chromatography. The reactionmixture is then poured into two liters of ice water and then neutralizedwith sodium bicarbonate. After three extractions with ether, the etherphase is dried over sodium sulphate and then concentrated. 38 g of anorange oil which corresponds to the expected product are obtained.

EXAMPLE B Synthesis of1-(5,8-methano-5,6,7,8-tetrahydro-2-naphthyl)ethyltriphenylphosphoniumbromide (formula XII with R₁, R₃, R₄ ═H and R' ═CH₃)

15 g of 2-acetylbenzonorbornene are dissolved in 75 cm³ of methanolcooled to 0° C. 3 g of sodium borohydride are added in small portionsand stirring is continued for 1 hour. When the starting material hasbeen converted (which is checked by thin-layer chromatography), thereaction mixture is concentrated to half its volume and is poured intoapproximately 250 cm³ of 1 N hydrochloric acid. The product is extractedtwice with ether. The organic phase is dried over magnesium sulphate andconcentrated under reduced pressure. The ¹ H nuclear magnetic resonancespectrum agrees with the expected structure. The 14 g of alcoholobtained in this way are dissolved in 75 cm³ of dichloromethane. 6 cm³of phosphorus tribromide are added dropwise at 0° C. Stirring iscontinued and the temperature is maintained at 0° C. for approximately 2hours; the reaction mixture is then poured into 300 cm³ of ice water andis extracted with dichloromethane. The organic phase is washed with asodium bicarbonate solution, dried and concentrated under reducedpressure. 15 g of bromo derivative are recovered. The ¹ H nuclearmagnetic resonance spectrum agrees with the expected structure. Theproduct obtained in this way is dissolved in 150 cm³ of anhydroustoluene. 16 g of triphenylphosphine are added and the reaction mixtureis refluxed in toluene for 24 hours. After cooling, the expected productseparates as an oil and crystallizes in ether.

27 g of triphenylphosphonium salt are recovered, i.e. an overall yieldof 65%.

Molecular mass found: 513.

Melting point: 156°-158° C.

EXAMPLE c Synthesis of ethyl 5-formyl-3-methyl-2,4-pentadienoate

First step: synthesis of ethyl 3-dimethylacetalisocrotonate

24 g of 50% weight strength sodium hydride, previously washed withhexane, suspended in 500 cm³ of anhydrous tetrahydrofuran are added, inan inert atmosphere, into a two-liter reactor fitted with a mechanicalstirrer. The suspension is cooled to 0° C. and approximately 1 cm³ ofcrown ether (15-crown-5) is added. A solution of 112 g of triethylphosphonoacetate and of 59 g of pyruvic aldehyde dimethyl acetal in 200cm³ of anhydrous tetrahydrofuran is added dropwise while the temperatureis maintained below 20° C. Evolution of gas and thickening of thereaction mixture are observed. After the addition (approximately 2hours), stirring is continued for 1 hour at ambient temperature. Thesolution is poured into approximately 1 liter of ice water and extractedwith ether. The organic phase is washed with a solution of sodiumchloride, dried and concentrated under reduced pressure. The expectedproduct is purified by distillation under reduced pressure: it boils at50-53° C. at a pressure of 0.13 millibar. 77 g of a mixture (20/80) ofcis-trans isomers are recovered (determination by ¹ H nuclear magneticresonance), corresponding to a yield of 82%.

Second step: synthesis of the 5-formyl-3-methyl-2,4-pentadienoate .

75 g of the product obtained in the first step are dissolved in 500 cm³of anhydrous hexane in a 1-liter round flask and the solution is heatedto 40° C. 1.8 cm³ of boron trifluoride diethyletherate are added and 30cm³ of ethyl vinyl ether are added in an inert atmosphere while thetemperature is maintained below 50° C. After addition, stirring iscontinued for 1 hour at 40°-50° C. 10 g of sodium bicarbonate are added,are filtered off and the liquid is concentrated under reduced pressure.The residue thus obtained is taken up with 350 cm³ of ethyl acetate.This solution is introduced into a round flask containing 60 g oforthophosphoric acid and 250 cm³ of distilled water. The reactionmixture is heated to the reflux temperature of ethyl acetate (70-75° C.)for 5 hours with intensive stirring and then concentrated under reducedpressure and extracted with 500 cm³ of toluene. The organic phase iswashed with a sodium bicarbonate solution and then dried andconcentrated under reduced pressure. 47 g of crude crystalline productare obtained. After recrystallization from hexane, 28 g of pure productcorresponding to the trans-trans structure are obtained.

The molecular mass found is 169. The melting point is 49°-50° C.

EXAMPLE A Preparation of 2-isobutyrylbenzonorbornene

48.6 cm³ of isobutyric anhydride are added to a solution of 35 g ofbenzonorbornene in 600 cm³ of methylene chloride. 77.8 g of aluminumchloride in solid form are then added in small portions at a temperatureof approximately 10° C.

The reaction is exothermic and the temperature of the mixture ismaintained at about 10° C. The solution, originally colorless, becomesbrown. When all the aluminum chloride has been added, thin-layerchromatography (TLC) is used to check that benzonorbornene has beencompletely converted. The reaction mixture is then poured into 1 literof ice water. The organic phase is separated by gravity, washed withsodium bicarbonate and dried over magnesium sulphate.

The solvent is distilled off under reduced pressure. 53 g of2-isobutyrylbenzonorbornene are obtained, the nuclear magnetic resonancespectrum of which agrees with the expected structure.

EXAMPLE B Preparation of 2-isobutylbenzonorbornene

40 g of 2-isobutyrylbenzonorbornene obtained in Example A and 80 cm³ ofhydrazine in 500 cm³ of butanol are placed in a round flask fitted witha condenser with a Dean-Stark water separator. The mixture is heated to150° C. The water-butanol azeotrope distils over. When the theoreticalquantity of water (43 cm³) has been removed, thin-layer chromatographyis used to check that 2isobutyrylbenzonorbornene has been converted tothe corresponding hydrazone. Butanol is then removed by distillationunder vacuum. The crude hydrazone is taken up with 500 cm³ of diethyleneglycol, to which 20 g of potassium hydroxide are added. The solutionobtained is then heated at 220° C. for 15 hours.

The reaction mixture is then poured into 2 liters of ice water, to which300 g of ammonium chloride are added.

This solution is then extracted three times with 350-cm³ portions ofethyl ether. The ether phases are combined, washed with water, driedover magnesium sulphate, and the solvent is removed by vacuumevaporation. 36.5 g of 2-isobutylbenzonorbornene are obtained andpurified by distillation at a pressure of 23 millibars. The boilingpoint at this pressure is 136° C. The nuclear magnetic resonancespectrum and thin-layer chromatography show that the product obtained(30 g) is pure.

EXAMPLE C Preparation of 2-ethylbenzonorbornene

A solution of 20 g of 2-acetylbenzonorbornene (prepared in the thirdstep of Example a) above) and of 10 cm³ of hydrazine hydrate in 100 cm³of butanol is heated at the boiling temperature of butanol. Thebutanol-water azeotrope is distilled off, and then butanol is evaporatedoff under reduced pressure.

The crude hydrazone thus obtained is dissolved directly in 100 cm³ ofethylene glycol, to which 5 g of potassium hydroxide are added and thewhole is heated at the reflux temperature of ethylene glycol until thehydrazone is completely converted.

The reaction mixture, at ambient temperature, is poured into water and2-ethylbenzonorbornene is extracted with methylene chloride. Themethylene chloride phase is washed with sodium bicarbonate, dried oversodium sulphate and concentrated. After evaporation of methylenechloride 15 g of 2-ethylbenzonorbornene are obtained, which are employedin the crude state for the following acylation reactions:

EXAMPLE D Preparation of 2-acetyl-3-isobutylbenzonorbornene (formula VIIin which R₃ ═isobutyl,

    R.sub.1 ═R.sub.4 ═H, R'═CH.sub.3)

24 g of aluminum chloride are added in small portions to a solution of30 g of 2-isobutylbenzonorbornene (prepared according to Example B) in500 cm³ of anhyorous methylene chloride and 12.8 cm³ of acetyl chloride,cooled to a temperature in the region of 10° C., while this temperatureis maintained.

At the end of addition, thin-layer chromatography is used to check thatall the starting material has been converted. The reaction mixture istreated as in Example A above and 35 g of2-acetyl-3-isobutylbenzonorbornene are obtained.

EXAMPLE E Preparation of 2-acetyl-3-ethylbenzonorbornene (Formula VII inwhich R₁ ═R₄ ═H, R₃ ═ethyl, R'═CH₃)

2-Ethylbenzonorbornene prepared according to Example C is treated withacetyl chloride and aluminum chloride in methylene chloride under thesame conditions as 2-isobutylbenzonorbornene in Example D above.

2-Ethylbenzonorbornene is converted quantitatively to2-acetyl-3-ethylbenzonorbornene.

EXAMPLE F Preparation of 2-acetyl-1,4-dibromobenzonorbornene (FormulaVII in which R₁ ═R₄ ═Br, R₃ ═H, R'═CH3)

14.3 g of aluminum chloride are added to a solution of 10 g of2-acetylbenzonorbornene in 130 cm³ of anhydrous methylene chloride,cooled at 0° C., followed by a dropwise addition of 5 cm³ of brominedissolved in 40 cm³ of methylene chloride. The solution is then stirredfor 48 hours at ambient temperature. At this stage most of the startingmaterial has been converted.

300 cm³ of water are then added to the reaction mixture. The methylenechloride solution is separated by gravity, washed with water containingbicarbonate, dried over sodium sulphate and concentrated. 18 of a crudeproduct are obtained and purified by passing through a column of silicagel. The expected product is eluted with a 95/5 hexane/ethyl acetatemixture.

After concentration of the eluate phases, 15 g of2-acetyl-1,4-dibromobenzonorbornene are obtained, the nuclear magneticresonance spectrum of which agrees with the structure.

EXAMPLE G Preparation of 2-acetyl-1,4-dimethoxybenzonorbornene

45 g of 1,4-dihydroxybenzonorbornene are added to a solution of 60 g ofpotassium tert-butylate in 200 cm³ of anhydrous dimethyl sulphoxide,which is stirred at ambient temperature and protected from atmosphericmoisture. After approximately 1 hour 36 cm³ of methyl iodide are thenadded dropwise.

The reaction is exothermic and the temperature is maintained between 20°and 30° C. by means of an ice bath. Thin-layer chromatography is thenused to check that the reaction is complete.

The reaction mixture is then poured into 300 cm³ of water and extractedtwice with ether. The ether phase is washed with water, dried oversodium sulphate and concentrated. 44 g of 1,4-dimethoxybenzonorborneneare obtained and used directly for the following acylation reaction.

23.5 g of aluminum chloride are added in small portions to a mixture of30 g of 1,4-dimethoxybenzonorbornene and 13.8 g of acetyl chloride in300 cm³ of methylene chloride. At this stage, a check is made that allthe starting material has been converted. The reaction mixture is pouredinto 300 cm³ of water. The organic phase is washed with sodiumbicarbonate, then with water, and dried over magnesium sulphate.

After evaporation of the solvent under reduced pressure 28 g of2-acetyl-1,4-dimethoxybenzonorbornene are obtained.

EXAMPLE H Preparation of 2-ethyl-1,4-dimethoxybenzonorbornene1'-triphenylphosphonium bromide

2-Acetyl-1,4-dimethoxybenzonorbornene of Example G is reduced withsodium borohydride to the corresponding alcohol. This alcohol isconverted quantitatively to a bromo derivative by reaction with PBr₃ andthe triphenyl phosphonium salt is obtained by heating this bromoderivative in the presence of an equivalent of triphenylphosphine intoluene.

The salt obtained is a crystalline material which melts between 160° and165° C. (slight decomposition commencing at 130° C.).

EXAMPLE I Preparation of 2-formylbenzonorbornene

(Formula (VII) in which R₁ ═R₃ ═R₄ R'═H) from benzonorbornene accordingto an operating procedure described in "Organic syntheses" CollectiveVol. V-p. 49, which deals with the formylation of2,4,6-trimethylbenzaldehyde.

9 cm³ of titanium tetrachloride (0.082 mole) are added to a solution of5.91 g (0.041 mole) of benzonorbornene in 50 cm³ of anhydrousdichloromethane stirred at 0° C., followed, dropwise, by a solutioncontaining 3.2 cm³ of dichloromethyl methyl ether (0.04 mole) in 10 cm³of anhydrous dichloromethane. The temperature is maintained at 0° C.throughout the addition and then the reaction mixture is allowed toreturn to ambient temperature. It is then poured onto 60 g of meltingice and extracted with 60 cm³ of dichloromethane. The organic phase isseparated by gravity, washed three times with 400-cm³ portions of water,dried over sodium sulphate and concentrated. 2-Formylbenzonorbornene isthen purified by distillation at a pressure of 0.027 bar (20 mm Hg). Itis a colourless liquid (B.p.˜144° C.-147° C./0.027 bar).

EXAMPLE J Preparation of 2-methylbenzonorbornene triphenylphosphoniumbromide

The phosphonium salt is obtained according to the same operatingprocedure as that described for Example H. After reduction, brominationand treatment with triphenylphosphine, 2-formylbenzonorbornene leads toa crystalline product which melts between 185° and 190° C.

EXAMPLE 1 Synthesis of all-trans ethyl7-(5,8-methano-5,6,7,8-tetrahydro-2-naphthyl)-3-methyl-2,4,6-octatrienoate(compound of formula (I) in which R₁, R₃, R₄ are hydrogens, R'═CH₃, andR" is a polyene chain, A₂ having the meaning COOC₂ H₅)

20 cm³ of n-butyllithium (1.6 M) are added dropwise in an inertatmosphere to a suspension of 10.25 g (0.02 M) of the bromide preparedin Example b in 100 cm³ of anhydrous ether. After the intensely redsolution has been stirred for 2 hours at ambient temperature, 3 cm³ ofdichloromethane are added to destroy excess butyllithium and 3.3 g ofthe ethyl ester prepared in Example C, dissolved in 20 cm³ ofdichloromethane, are added under protection against light. Stirring iscontinued for 2 hours at ambient temperature. The reaction mixture ispoured into 150 cm³ of an ammonium chloride solution and extracted withthree times 100 cm³ of ether. The organic phase is dried over magnesiumsulphate and concentrated under reduced pressure. A yellow oil isobtained which is purified by being passed through a column of silicagel (eluent: 95/5 hexane/ethyl acetate). 3.9 g of a yellow oil areobtained, yielding, after crystallization from a hexane/methanolmixture, 2.1 g (31%) of the expected alltrans ester. The ¹ H 250 MHznuclear magnetic resonance spectrum agrees with the expected structure.

Molecular mass found: 322.

Melting point: 78°-80° C.

EXAMPLE 2 Synthesis of all-trans 7-(5,8-methano-5,6,7,8-tetrahydro-2-naphthyl)-3-methyl-2,4,6-octatrienoic acic(compound of formula (I) in which R₁, R₃, R₄ are hydrogens, R'═CH₃, R"is a polyene chain, in which A₂ has the meaning COOH)

1.5 g of the ethyl ester of Example 1 are dissolved, while protectedagainst light, in 20 cm³ of ethanol at 50° C. 20 cm³ of a 6 N aqueouspotassium hydroxide solution are added and the mixture is stirred for 3hours while the temperature is maintained at 50° C. Methanol isevaporated off under reduced pressure and the aqueous phase is acidifiedwith 2 N hydrochloric acid. A precipitate is formed, which is extractedwith ether. The organic phase is dried over magnesium sulphate andconcentrated under reduced pressure. The expected product crystallizesfrom hexane. 1.1 g of pure product are obtained (yield: 80%).

Molecular mass found: 294.

Melting point: 181° C.

Analysis of the product obtained gives the following results:

    ______________________________________                                        Analysis  C             H      O                                              ______________________________________                                        Theory    81.59         7.53   10.87                                          Found     81.46         7.56   10.66                                          ______________________________________                                    

EXAMPLE 3 Synthesis of N-ethyl all-trans7-(5,8-methano-5,6,7,8-tetrahydro-2-naphthyl)-3-methyl-2,4,6-octatrienoamid(compound of formula (I) in which R₁, R₃, R₄ are hydrogens, R'═CH₃, R"is a polyene chain, in which A₂ has the meaning CONHC₂ H₅)

200 mg of the product of Example 2 are dissolved in approximately 5 cm³of anhydrous toluene at 50° C. 65 mg of phosphorus trichloride are addedand the temperature is maintained at 45°-50° C. for 15 minutes. Theyellow solution thus obtained is added dropwise, under protectionagainst light, to a solution of 5 cm³ of ethylamine in 20 cm³ ofanhydrous toluene. During the addition, the temperature of the reactionmixture is maintained below 10° C. After one night at ambienttemperature the solution is poured into 100 cm³ of water and extractedwith ether. The organic phase is washed and dried and then concentratedunder reduced pressure. The residue is purified by chromatography onsilica gel (eluent=50/50 hexane/ethyl acetate). After recrystallizationfrom hexane 150 mg of the expected product are recovered in the form ofa white powder.

Molecular mass found: 321.

Melting point: 129° C.

Analysis of the product obtained gives the following results:

    ______________________________________                                                   C    H          N      O                                           ______________________________________                                        Calculated for                                                                             82.31  8.48       4.36 4.98                                      C.sub.22 H.sub.27 O                                                           Found        82.24  8.41       4.36 5.22                                      ______________________________________                                    

EXAMPLE 4 Synthesis oftrans-5,8-methano-5,6,7,8-tetrahydro-2-(β-methylstyryl)naphthalene(compound of formula (I) in which R₁, R₃, R₄ are hydrogens, R'═CH₃, R"denotes a benzene ring, A₃ having the meaning H)

1.55 cm³ of benzaldehyde and 4.2 g of potassium carbonate are added to asuspension of 7.5 g of the bromide of Example b, in 75 cm³ ofisopropanol. The reaction mixture is heated to reflux for 3 hours andthen filtered on sintered glass and concentrated under reduced pressure.4.2 of a colorless oil are obtained, which is purified by chromatographyon silica gel (eluent=95/5 hexane/ethyl acetate). 2 g of an oil areobtained, which crystallizes in isopropanol in the freezer.

Molecular mass found: 260

Melting point: 33° C.

Analysis of the product obtained gives the following results:

    ______________________________________                                        Analysis         C      H                                                     ______________________________________                                        Theory           92.26  7.74                                                  Found            92.24  7.79                                                  ______________________________________                                    

EXAMPLE 5 Synthesis oftrans-5,8-methano-5,6,7,8-tetrahydro-2-(4'-methyl-β-methylstyryl)naphthalene(compound of formula (I) in which R₁, R₃, R₄ are hydrogens, R'═CH₃, R"denotes a benzene ring, A₃ having the meaning CH₃)

1.70 cm³ of toluylaldehyde and 4.2 g of potassium carbonate are added toa suspension of 7.5 g of the bromide of Example b, in 70 cm³ ofisopropanol. The reaction mixture is heated to the reflux temperature ofisopropanol for 4 hours and then filtered on sintered glass andconcentrated under reduced pressure. 2.3 g of a colorless oil areobtained after chromatography on silica gel (eluent=hexane). The productcrystallizes in isopropanol in the freezer. The ¹ H nuclear magneticresonance spectrum corresponds to the expected trans structure.

Molecular mass found: 274

Melting point: 59° C.

EXAMPLE 6 Synthesis oftrans-5,8-methano-5,6,7,8-tetrahydro-2-(4'-methylsulphonyl-β-methylstyryl)naphthalene(compound of formula (I) in which R₁, R₃, R₄ are hydrogens, R'═CH₃, R"denotes a benzene ring, A₃ having the meaning SO₂ CH₃)

1.8 g of 4-methylsulphonylbenzaldehyde and 2.90 g of potassium carbonateare added to a suspension of 4.2 g of the bromide of Example b in 60 cm³of isopropanol. The reaction mixture is heated to the reflux temperatureof isopropanol for 4 hours and then filtered on sintered glass. 1.65 gof a product which crystallizes in the filtrate are recovered. Theproduct is purified by chromatography on silica gel(eluent=dichloromethane). 1.2 g of white crystals are obtained. The ¹ Hnuclear magnetic resonance spectrum corresponds to the expected transstructure.

Molecular mass found: 338

Melting point: 152° C.

EXAMPLE 7

Preparation of4-[cis-2-(1,4-dibromo-5,8-methano-5,6,7,8-tetrahydro-2-naphthyl)propenyl]benzoicacid of formula: ##STR31##

Four drops of crown ether (15 C 5) are added at ambient temperature to astirred solution of 0.5 g of sodium hydride (50% suspension in oil) in50 cm³ of anhydrous tetrahydrofuran, protected from light and fromatmospheric moisture, and then, at a temperature of 10° C., a solutioncontaining the mixture of 3 g of 2-acetyl-1,4-dibromobenzonorbornene and2.9 g of diethyl 4-ethoxycarbonyl benzylphosphonate is added dropwise.The progress of the reaction mixture is followed by thin-layerchromatography. After 5 hours at ambient temperature 5 cm³ of ethanolare added to destroy a possible residue of unreacted sodium hydride. Thereaction mixture is then poured into 200 cm³ of 2 N hydrochloric acidand extracted with ethyl ether. The ether phase is dried over magnesiumsulphate, and evaporated to dryness.

Ethyl4-[cis-2-(1,4-dibromo-5,8-methano-5,6,7,8-tetrahydro-2-naphthyl)propenyl]benzoateis obtained as a brown oil which is treated directly at 50° C. in amixture consisting of 30 cm³ of ethanol and 30 cm³ of 6 N potassiumhydroxide for 3 hours while protected against light. Ethanol is thenevaporated off. The basic aqueous phase is diluted with 100 cm³ of waterand extracted three times with ether, which enables some impurities tobe extracted.

The aqueous phase is separated by gravity, and then acidified to pH≃1; alight-yellow precipitate forms. It is filtered off, washed with waterand twice with 10-cm³ portions of ether. 1.7 g of4-[cis-2-(1,4-dibromo-5,8-methano-5,6,7,8-tetrahydro-2-naphthyl)propenyl]benzoicacid are obtained, the structure of which is confirmed by a ¹ H 250 MHzspectrum. It is a light-beige solid melting at 267° C.

Analysis of the product obtained gives the following results:

    ______________________________________                                                      Calculated for                                                  Analysis      C.sub.21 H.sub.18 Br.sub.2 O.sub.2                                                        Found                                               ______________________________________                                        C %           54.57       54.32                                               H %           3.92        3.86                                                Br %          34.58       34.50                                               O %           6.92        6.72                                                ______________________________________                                    

EXAMPLE 8 Preparation of ethyl4-[cis-2-(1,4-dibromo-5,8-methano-5,6,7,8-tetrahydro-2-naphthyl)propenyl]benzoateof formula ##STR32##

A solution of 0.5 g of the above acid in 30 cm³ of ethanol is heated toreflux in the presence of a gram of para-toluenesulphonic acid underprotection against light and in an inert atmosphere. Five hours arenecessary to convert all the acid to the corresponding ethyl ester.Ethanol is removed by evaporation under vacuum. The crude ester isdissolved in 50 cm³ of methylene chloride. The solution is washed withpotassium bicarbonate and then with water; it is dried over magnesiumsulphate and concentrated. The ethyl ester thus obtained is crystallizedfrom methanol. 0.2 g of cream-coloured crystals melting at 79° C. isobtained.

The ¹ H 250 MHz nuclear magnetic resonance spectrum confirms the cisstructure of the product obtained.

EXAMPLE 9 Preparation of ethyl4-[cis-2-(3-isobutyl-5,8-methano-5,6,7,8-tetrahydro-2-naphthyl)propenyl]benzoateof formula ##STR33##

Four drops of crown ether (15 C 5) are added at ambient temperature to astirred solution of 1 g of sodium hydride (50% suspension in oil) in 50cm³ of anhydrous tetrahydrofuran, protected against light andatmospheric moisture. Then, a solution of 30 cm³ of tetrahydrofurancontaining a mixture of 5 g of diethyl 4-ethoxycarbonylbenzylphosphonate and 4.03 g of 2-acetyl-3-isobutylbenzonorbornene isadded at ambient temperature.

After 1 hour at the boiling point of tetrahydrofuran, additional 0.5 gof phosphonate is added.

The mixture is stirred further for 4 hours at 70° C. At this stage thereaction is complete. The unreacted sodium hydride is destroyed byadding 5 cm³ of ethanol.

The reaction mixture is then poured into 200 cm³ of water and thenextracted with ether. The ether phase is washed, dried and concentrated.The product obtained is purified by chromatography on silica gel andeluted with methylene chloride.

2.5 g of a viscous liquid are obtained, the nuclear magnetic resonancespectrum of which corresponds chiefly to ethyl4-[cis-2-(3-isobutyl-5,8-methano-5,6,7,8-tetrahydro-2-naphthyl)propenyl]benzoate.

EXAMPLE 10 Preparation of4-[cis-2-(3-isobutyl-5,8-methano-5,6,7,8-tetrahydro-2-naphthyl)propenyl]benzoicacid ##STR34##

A mixture of 20 cm³ of ethanol, of 20 cm³ of 6 N potassium hydroxide and2 g of the above ester is heated at 50° C. for 2 hours while protectedagainst light. Alcohol is evaporated off, the residual solution isdiluted with 100 cm³ of water and extracted twice with 25 cm³ portionsof ether.

The aqueous phase is acidified by adding 3 N hydrochloric acid andextracted three times with 30-cm³ portions of ether.

The ether phases are combined, dried over magnesium sulphate andconcentrated. 1.2 g of acid containing the two cis and trans isomers isobtained. 0.6 g of4-[cis-2-(3-isobutyl-5,8-methano-5,6,7,8-tetrahydro-2-naphthyl)propenyl]benzoicacid is isolated by crystallization from 10 cm³ of methanol. These arecream-colored crystals the melting point of which is 191°C.

    ______________________________________                                                      Calculated for                                                  Analysis      C.sub.25 H.sub.28 O.sub.2                                                                 Found                                               ______________________________________                                        C %           83.29       83.09                                               H %           7.83        7.85                                                O %           8.88        8.89                                                ______________________________________                                    

EXAMPLE 11 Preparation of ethyl4-[cis-2-(5,8-methano-5,6,7,8-tetrahydro-2-naphthyl)-3-methylbutenyl]benzoateof formula ##STR35##

Under experimental conditions identical to those described in Example 7,3 g of 2-isobutyrylbenzonorbornene and 5 g of diethyl 4-ethoxycarbonylbenzylphosphonate in 50 cm³ of anhydrous tetrahydrofuran are treatedwith 0.87 g of sodium hydride (50% suspension in oil) in the presence ofa few drops of crown ether.

The mixture is heated under reflux for 5 hours and then treated inaccordance with Example 7.

After evaporation of the ether extracts, 5 g of the expected produce areobtained. It is purified by being passed through a column of silica geland eluted with a 97/3 hexane/ethyl acetate mixture.

3 g of ethyl4-[cis-2-(5,8-methano-5,6,7,8-tetrahydro-2-naphthyl)-3-methylbutenyl]benzoateare obtained, the ¹ H 250 MHz nuclear magnetic resonance spectrum ofwhich confirms the cis structure.

    ______________________________________                                                      Calculated for                                                  Analysis      C.sub.25 H.sub.28 O.sub.2                                                                 Found                                               ______________________________________                                        C %           83.29       83.27                                               H %           7.83        7.90                                                O %           8.88        8.86                                                ______________________________________                                    

EXAMPLE 12 Preparation of ethyl4-[trans-2-(5,8-methano-5,6,7,8-tetrahydro-2-naphthyl)-3-methylbutenyl]benzoateof formula ##STR36##

A solution of 3 g of the cis ester prepared in accordance with Example11 in 400 cm³ of methanol is exposed to natural light. The cis→transisomerization is followed by H.P.L.C.

After 24 hours' exposure approximately 80% of cis isomer is converted totrans. The solution is concentrated to approximately 50 cm³ and placedat -20°C. The expected trans isomer crystallizes. It is filtered off,dried and analyzed. 2 g of ethyl4-[trans-2-(5,8-methano-5,6,7,8-tetrahydro-2-naphthyl)-3-methylbutenyl]benzoateare obtained. The trans structure is confirmed by the ¹ H 250 MHznuclear magnetic resonance spectrum. It is a white solid the meltingpoint of which is 65° C.

EXAMPLE 13 Preparation of4-[trans-2-(5,8-methano-5,6,7,8-tetrahydro-2-naphthyl)-3-methylbutenyl]benzoicacid ##STR37##

30 cm³ of a 6 N aqueous potassium hydroxide solution are added to asuspension of 1 g of the above ester prepared in accordance with Example12, in 30 cm³ of absolute alcohol. The mixture is stirred for 2 hours at60° C. while protected from light. At this stage all the ester issaponified. The mixture is poured into 70 cm³ of water and extractedtwice with ether. The aqueous phase is then acidified to pH≃1.

The expected acid is extracted with ether. The ether phase is washed,dried over magnesium sulphate, filtered and then concentrated underreduced pressure. The solid obtained is recrystallized from 20 cm³ ofmethanol at -20° C. The crystals are filtered off and dried. 600 mg of4-[trans-2-(5,8-methano-5,6,7,8-tetrahydro-2-naphthyl)-3-methylbutenyl]benzoicacid are obtained, the melting point of which is 161° C.

    ______________________________________                                                      Calculated for                                                  Analysis      C.sub.23 H.sub.24 O.sub.2                                                                 Found                                               ______________________________________                                        C %           83.10       82.98                                               H %           7.27        7.30                                                O %           9.63        9.45                                                ______________________________________                                    

EXAMPLE 4 Preparation of4-[cis-2-(1,4-dimethoxy-5,8-methano-5,6,7,8-tetrahydro-2-naphthyl)propenyl]benzoicacid ##STR38##

A mixture of 1.05 g of sodium hydride (50% in oil), of a few drops ofcrown ether 15 crown 5 in 50 cm³ of anhydrous tetrahydrofuran is stirredin an inert atmosphere for half an hour at ambient temperature. Then, atabout 10° C., a solution of 4.5 g of2-acetyl-1,4-dimethoxybenzonorbornene (prepared in accordance withExample G) and of 6 g of diethyl 4-ethoxycarbonyl benzylphosphonate in50 cm³ of tetrahydrofwran is added dropwise. The mixture is then heatedunder reflux for 5 hours. 5 cm³ of acetic acid are then added at ambienttemperature and the mixture is treated in accordance with Example 1.After purification by passing through a column of silica gel, 4.1 g ofethyl 4-[cis-2-(5,8-methano-5,6,7,8-tetrahydro-2-naphthyl)propenyl]benzoate are obtained as a mixture with its transisomer. This mixture, dissolved in 40 cm³ of ethanol is treated directlywith 40 cm³ of 6 N aqueous potassium hydroxide at a temperature of 50°C. until the complete conversion to the corresponding acid. The alcoholis evaporated off. The aqueous phase is extracted once with ether, andthen acidified to pH≃1 and reextracted with ether several times. Theorganic phase is dried and then concentrated. The product obtained isthen crystallized from the minimum quantity of acetonitrile. 1 gram ofwhite crystals melting at 212° C. is isolated in this manner. Thenuclear magnetic resonance spectrum corresponds to the structure of4-[cis-2-(1,4-dimethoxy-5,8-methano-5,6,7,8-tetrahydro-2-naphthyl)propenyl]benzoicacid.

To obtain the corresponding trans isomer, the mixture of Z and E isomersobtained after saponification, followed by acidification, is taken updirectly in methanol. In this solvent, the trans acid crystallizesfirst.

4-[trans-2-(1,4-Dimethoxy-5,8-methano-5,6,7,8-tetrahydro-2-naphthyl)propenyl]benzoicacid is a white solid melting at 180° C.

EXAMPLE 15 Preparation of all-trans7-(5,8-methano-5,6,7,8-tetrahydro-2-naphthyl)-3-methyl-2,4,6-heptatrienoicacid ##STR39##

5 g of the phosphonium salt of Example J are suspended intetrahydrofuran and treated with 6 cm³ of butyllithium (2.5 M). Afterthe intensely red solution has been stirred for 2 hours at ambienttemperature, 1 cm³ of dichloromethane is added, followed by 1.85 g ofethyl 5-formyl-3-methyl-2,4-pentadienoate in solution indichloromethane, protected against light. After 1 hour's reaction atambient temperature, the reaction mixture is hydrolyzed by addition ofacetic acid. The solution is concentrated under reduced pressure and theresidue is purified by chromatography on silica gel. 3 g of a yellow oilare obtained, the NMR spectrum of which corresponds to a mixture of cisand trans ethyl7-(5,8-methano-5,6,7,8-tetrahydro-2-naphthyl)-3-methyl-2,4,6-heptatrienoate.This oil is heated at 50° C. in a mixture of 50 cm³ of ethanol and 50cm³ of 6 N potassium hydroxide. Heating is continued (approximately 4 h)until the starting material has completely disappeared. The reactionmixture is concentrated under reduced pressure and acidified with 2 Nhydrochloric acid. The product obtained is filtered off and crystallizedfrom methanol. 500 mg of a yellow product are recovered, the ¹ H 250 MHzNMR spectrum of which corresponds to the expected structure and themelting point of which is 199°-201° C.

EXAMPLE 16 Preparation of all-trans ethyl7-(1,4-dimethoxy-5,8-methano-5,6,7,8-tetrahydro-2-naphthyl)-3-methyl-2,4,6-octatrienoate##STR40##

5 cm³ of n-butyllithium (2.5 M) are added in an inert atmosphere to asuspension of 5 g of the phosphonium salt of Example H in 100 cm³ oftetrahydrofuran. After 2 hours' stirring at ambient temperature, thestarting salt is found to have dissolved completely and an intense redcoloration is observed. 1.5 g of ethyl5-formyl-3-methyl-2,4-pentadienoate are then added is a solution indichloromethane, protected against light. After reaction of the startingaloehyde, the reaction mixture is hydrolyzed with acetic acid. Thesolution is concentrated under reduced pressure, and the residue ispurified by chromatography on silica gel. A pure fraction of a yellowoil is obtained, the ¹ H NMR spectrum of which corresponds to theexpected all-trans structure.

EXAMPLE 17 Preparation of all-trans7-(1,4-dimethoxy-5,8-methano-5,6,7,8-tetrahydro-2-naphthyl)-3-methyl-2,4,6-oxtatrienoicacid ##STR41##

A mixture of 1 g of the ester of Example 16, 25 cm³ of ethanol and 25cm³ of 6 N aqueous potassium hydroxide is heated at 50° C. forapproximately 2 hours. After evaporation of the alcohol under reducedpressure, the aqueous phase is acidified with 2 N hydrochloric acid andthe expected product is extracted with ethyl acetate. Afterrecrystallisation from ethanol, 350 mg of a yellow product arerecovered, the structure of which in ¹ H 250 MHz NMR agrees with theexpected all-trans structure and the melting point of which is 193°-195°C.

EXAMPLE 18

The following composition is prepared:

    ______________________________________                                        Compound of Example 2   0.1 g                                                 Polyethylene glycol (average molecular                                                               60.0 g                                                 weight = 400)                                                                 Polyethylene glycol (average molecular                                                               25.0 g                                                 weight = 4,000)                                                               Paraffin oil q.s.      100.0 g                                                ______________________________________                                    

In this way a suspension forming a water-removable ointment is obtained.This preparation is employed on skins with acne, dermatosis or psoriasisand is applied once to three times daily; good results are obtained overa period of between 6 and 12 weeks depending on the severity of the casetreated.

EXAMPLE 19

The following composition is prepared:

    ______________________________________                                        Compound of Example 1  0.15 g                                                 Mixture of emulsifiable lanolin                                                                      40.0 g                                                 alcohols and waxes and of refined oils                                        based on hydrocarbons sold by B.D.F.                                          Medical under the name of "Eucerin                                            anhydre"                                                                      Stabilizers q.s.                                                              Sterile demineralized water q.s.                                                                     100.0 g                                                ______________________________________                                    

In this way a nonionic suspension forming a cream is obtained. Thiscream is employed for the treatment of ichthyosis and is applied once tothree times daily; good results are obtained over a period of between 6and 12 weeks depending on the severity of the case treated.

EXAMPLE 20

The following composition is prepared:

    ______________________________________                                        Compound of Example 3                                                                               1.0 g                                                   Sodium dodecylsulphate                                                                              0.78 g                                                  1,2-Propanediol       1.56 g                                                  Cetyl alcohol        19.50 g                                                  Thick paraffin oil   19.50 g                                                  Stabilizers q.s.                                                              Sterile demineralized water q.s.                                                                   100.00 g                                                 ______________________________________                                    

In this way an anionic suspension forming a cream is obtained. Thiscream is employed for the treatment of dry acnes and confined patches ofpsoriasis and is applied once to three times daily; good results areobtained over a period of between 6 and 12 weeks, depending on theseverity of the case treated.

EXAMPLE 21

The following composition is prepared:

    ______________________________________                                        Compound of Example 17                                                                             0.050 g                                                  Wheat starch         0.265 g                                                  Dicalcium phosphate  0.040 g                                                  Lactose ("fine crystals" grade)                                                                    0.040 g                                                  Talc                 0.010 g                                                  Magnesium stearate   0.005 g                                                  ______________________________________                                    

In this way 0.4 g tablets are obtained. These tablets are to be takentwice daily for the treatment of rheumatoid psoriasis and a significantimprovement is observed after approximately 30 days.

EXAMPLE 22

The following composition is prepared:

    ______________________________________                                        Compound of Example 16  0.05   g                                              Glycerin                2.40   g                                              70% Sorbitol            2.00   g                                              Sucrose                 0.10   g                                              Sodium para-hydroxybenzoate                                                                           0.08   g                                              Flavoring q.s.                                                                Purified water q.s.     10.00  ml                                             ______________________________________                                    

In this way a drinkable suspension is obtained which is packaged in10-ml phials. This drinkable suspension is employed for the treatment ofparticularly severe cases of acne and of psoriatic rheumatism by one tothree ingestions daily; a significant improvement is obtained afterapproximately 30 days.

EXAMPLE 23

The following composition is prepared:

    ______________________________________                                        Compound of Example 2    0.001  g                                             Sodium chloride          0.8    g                                             Citric acid/sodium hydroxide buffer                                                                    pH     6                                             q.s.                                                                          Water for injection q.s. 100    ml                                            ______________________________________                                    

In this way a solution is obtained which can be injected by intravenousroute. This solution is employed for the treatment of epithelial tumors.

EXAMPLE 24

The following composition is prepared:

    ______________________________________                                        Compound of Example 13    0.1    g                                            Polyethylene glycol (average molecular                                                                  60.0   g                                            weight = 400)                                                                 Polyethylene glycol (average molecular                                                                  25.0   g                                            weight = 4,000)                                                               Paraffin oil q.s.         100.0  g                                            ______________________________________                                    

In this way a suspension forming a water-removable ointment is obtained.This preparation is employed on skins with acne, dermatosis or psoriasisand is applied once to three times daily; good results are obtained overa period of between 6 and 12 weeks, depending on the severity of thecase treated.

EXAMPLE 25

The following composition is prepared:

    ______________________________________                                        Compound of Example 14 (trans)                                                                          0.15   g                                            Mixture of emulsifiable lanolin alcohols                                                                40.0   g                                            and waxes and refined oils based on                                           hydrocarbons sold by B.D.F. Medical                                           under the name of "Eucerin anhydre"                                           Stabilizers q.s.                                                              Sterile demineralized water q.s.                                                                        100.0  g                                            ______________________________________                                    

In this way a nonionic suspension forming a cream is obtained. Thiscream is employed for the treatment of ichthyosis and applied once tothree times daily; good results are obtained over a period of between 6and 12 weeks, depending on the severity of the case treated.

EXAMPLE 26

An antiseborrhoeic lotion is prepared in the following manner:

0.1 of the compound of Example 4 is added to a solution consisting of 10cm³ of 95° ethanol and 30 cm³ of polyethylene glycol (molecular mass:approximately 400), containing 20 mg of butylated hydroxytoluene.

After dissolution with stirring, the lotion is applied all over thehair.

The treatment is preferably carried out twice daily. After 15 days'treatment a satisfactory result is observed.

EXAMPLE 27

An antiseborrhoeic lotion is prepared in the following manner:

0.1 g of the compound of Example 9 is added to a solution consisting of10 cm³ of 95° ethanol and cm³ of polyethylene glycol (molecular mass:approximately 400), containing 20 mg of butylated hydroxytoluene.

After dissolution with stirring, the lotion is applied all over thehair.

The treatment is preferably carried out twice daily. After 15 days'treatment a satisfactory result is noted.

EXAMPLE 28

An anti-seborrhoeic cream is prepared by producing the followingformulation:

    ______________________________________                                        Polyoxyethylene stearate (40 moles of                                                                     4      g                                          ethylene oxide sold under the name                                            "Myrj 52" by "Atlas"                                                          Mixture of sorbitan and sorbitol laurates,                                                                1.8    g                                          polyoxyethylenated with 20 moles of ethylene                                  oxide, sold under the name "Tween 20" by                                      "Atlas"                                                                       Mixture of glycerol mono- and distearate sold                                                             4.2    g                                          under the name "Geleol" by "Gattefosse"                                       Propylene glycol            10     g                                          Butylated hydroxyanisole    0.01   g                                          Butylated hydroxytoluene    0.02   g                                          Ceto-stearyl alcohol        6.2    g                                          Preserving agents           qs                                                Perhydrosqualene            18     g                                          Mixture of caprylic-capric triglycerides sold                                                             4      g                                          under the name "Miglyol 812" by "Dynamit Nobel"                               S-Carboxymethylcysteine     3      g                                          99% Triethanolamine         2.5    g                                          Compound of Example 6       0.02   g                                          Water q.s.                  100    g                                          ______________________________________                                    

EXAMPLE 29

An anti-seborrhoeic cream is prepared by producing the followingformulation:

    ______________________________________                                        Polyoxyethylene stearate (40 moles of                                                                    4       g                                          ethylene oxide) sold under the name                                           "Myrj 52" by "Atlas"                                                          Mixture of sorbitan and sorbitol laurates,                                                               1.8     g                                          polyoxyethylenated with 20 moles of ethylene                                  oxide, sold under the name "Tween 20" by                                      "Atlas"                                                                       Mixture of glycerol mono- and distearate sold                                                            4.2     g                                          under the name "Geleol" by "Gattefosse"                                       Propylene glycol           10      g                                          Butylated hydroxyanisole   0.01    g                                          Butylated hydroxytoluene   0.02    g                                          Ceto-stearyl alcohol       6.2     g                                          Preserving agents          q.s.                                               Perhydrosqualene           18      g                                          Mixture of caprylic-capric triglycerides sold                                                            4       g                                          under the name "Miglyol 812" by "Dynamit Nobel"                               2-Benzylthioethylammonium 5-amino-5-carboxy-3-                                                           3       g                                          thiapentanoate                                                                Compound of Example 2      0.02    g                                          Water q.s.                 100     g                                          ______________________________________                                    

EXAMPLE 30

An anhydrous lotion is prepared by mixing the following ingredients:

    ______________________________________                                        Ethanol                  45     g                                             Propylene glycol         44.05  g                                             Polytetrahydrofuran dimethyl ether                                                                     10     g                                             Compound of Example 3    0.1    g                                             Butylated hydroxytoluene 0.05   g                                             ______________________________________                                    

EXAMPLE 31

A screening gel is prepared by mixing the following ingredients:

    ______________________________________                                        Ethyl alcohol              44     g                                           Propylene glycol           44.15  g                                           Acrylic acid polymer sold under the name                                                                 1      g                                           "Carbopol 940" by "Goodrich Chemical Co."                                     99% Triethanolamine        0.5    g                                           Butylated hydroxyanisole   0.01   g                                           Butylated hydroxytoluene   0.02   g                                           Purified water             10     g                                           Compound of Example 15     0.02   g                                           3,3'-Terephthalylidene-10,10'-dicamphosul-                                                               0.5    g                                           phonic acid dihydrate                                                         ______________________________________                                    

EXAMPLE 32

An anti-acne cream is prepared by mixing the following ingredients:

    ______________________________________                                        Mixture of glycerol and polyethylene glycol                                                              15     g                                           (75 mol) stearates sold under the name "Gelot                                 64" by "Gattefosse"                                                           Kernel oil polyoxyethylenated with 6 moles of                                                            8      g                                           ethylene oxide, sold under the name "Labrafil                                 M 2130 CS" by "Gattefosse"                                                    Perhydrosqualene           10     g                                           Colorant                   q.s.                                               Preserving agents          q.s.                                               Perfumes                   q.s.                                               Thioxolone                 0.4    g                                           Polyethylene glycol of molecular mass 400                                                                8      g                                           Purified water             58.5   g                                           Disodium ethylenediaminetetraacetate                                                                     0.05   g                                           Compound of Example 2      0.05   g                                           ______________________________________                                    

EXAMPLE 33

A lotion for regrowth of hair is prepared by mixing the followingingredients:

    ______________________________________                                        Propylene glycol           20     g                                           Ethanol                    34.92  g                                           Polyethylene glycol of molecular mass 400                                                                40     g                                           Water                      4      g                                           Butylated hydroxyanisole   0.01   g                                           Butylated hydroxytoluene   0.02   g                                           Compound of Example 2      0.05   g                                           Minoxidil                  1      g                                           ______________________________________                                    

EXAMPLE 34

An anti-acne cream is prepared by mixing the following ingredients:

    ______________________________________                                        Polyoxyethylene stearate (40 mol of ethylene                                                            4      g                                            oxide) sold under the name "Myrj 52" by                                       "Atlas"                                                                       Mixture of sorbitan and sorbitol laurates,                                                              1.8    g                                            polyoxyethylenated with 20 moles of ethylene                                  oxide, sold under the name "Tween 20" by                                      "Atlas"                                                                       Mixture of glycerol mono- and distearate sold                                                           4.2    g                                            under the name "Geleol" by "Gattefosse"                                       Propylene glycol          10     g                                            Butylated hydroxyanisole  0.01   g                                            Butylated hydroxytoluene  0.02   g                                            Ceto-stearyl alcohol      6.2    g                                            Preserving agents         q.s.                                                Polytetrahydrofuran dimethyl ether                                                                      18     g                                            Mixture of caprylic-capric triglycerides sold                                                           4      g                                            under the name "Miglyol 812" by "Dynamit                                      Nobel"                                                                        Compound of Example 2     0.02   g                                            Water q.s.                100    g                                            ______________________________________                                    

EXAMPLE 35

An anti-acne gel is prepared by producing the following formulation:

    ______________________________________                                        Compound of Example 2      0.05   g                                           Isopropyl alcohol          40     g                                           Acrylic acid polymer sold under the name                                                                 1      g                                           "Carbopol 940" by "Goodrich Chemical Co."                                     99% Triethanolamine        0.6    g                                           Butylated hydroxyanisole   0.01   g                                           Butylated hydroxytoluene   0.02   g                                           Thioxolone                 0.5    g                                           Propylene glycol           8      g                                           Purified water q.s.        100    g                                           ______________________________________                                    

EXAMPLE 36

A screening cream is prepared by producing the following formulation:

    ______________________________________                                        Polyoxyethylene stearate (40 moles of ethylene                                                           4.4    g                                           oxide) sold under the name "Myrj 52" by                                       "Atlas"                                                                       Ceto-stearyl alcohol       6.2    g                                           Mixture of glycerol mono- and distearate sold                                                            4.3    g                                           under the name "Geleol" by "Gattefosse"                                       Butylated hydroxyanisole   0.05   g                                           Butylated hydroxytoluene   0.05   g                                           Xanthane gum               0.25   g                                           Isopropyl myristate        4      g                                           Compound of Example 10     0.1    g                                           3,3'-Terephthalylidene-10,10'-dicamphosul-                                                               2      g                                           phonic acid dihydrate                                                         99% Triethanolamine        1      g                                           Demineralized water q.s.   100    g                                           ______________________________________                                    

EXAMPLE 37

This is an anti-acne kit comprising two parts:

a) a gel is prepared by producing the following formulation:

    ______________________________________                                        Ethyl alcohol              48.4   g                                           Propylene glycol           50     g                                           Acrylic acid polymer sold under the name                                                                 1      g                                           "Carbopol 940" by "Goodrich Chemical Co."                                     99% Diisopropanolamine     0.3    g                                           Butylated hydroxyanisole   0.05   g                                           Butylated hydroxytoluene   0.05   g                                           α-Tocopherol         0.1    g                                           Compound of Example 3      0.1    g                                           ______________________________________                                    

b) a gel is prepared by producing the following formulation:

    ______________________________________                                        Ethyl alcohol              5      g                                           Propylene glycol           5      g                                           Disodium ethylenediaminetetraacetate                                                                     0.05   g                                           Acrylic acid polymer sold under the name                                                                 1      g                                           "Carbopol 940" by "Goodrich Chemical Co."                                     99% Triethanolamine        1      g                                           Sodium laurylsulphate      0.1    g                                           Purified water             75.05  g                                           25% Aqueous benzoyl peroxide                                                                             12.8   g                                           ______________________________________                                    

A mixture of the two gels, weight for weight, is made at the time ofuse.

It is obvious that the examples of implementation described above arenot restrictive in any manner and may give rise to all desirablemodifications, without departing thereby from the scope of theinvention.

We claim:
 1. A benzonorbornene derivative of formula (I) or an isomer orsalt thereof having the formula ##STR42## wherein R₁, R₃ and R₄ eachindependently represent hydrogen, C₁ -C₈ alkoxy, halogen, C₁ -C₈ alkyl,C₁ -C₈ acycloxy or hydroxyl,R' is hydrogen or C₁ -C₆ alkyl and R ishydrogen, C₁ -C₆ alkyl, --SR₅, --SOR₅ or --SO₂ R₅, wherein R₅ is C₁ -C₆alkyl.
 2. The benzonorbornene derivative of claim 1 selected from thegroup consistingoftrans-5,8-methano-5,6,7,8-tetrahydro-2-(β-methylstyrl) naphthalene,trans-5,8-methano-5,6,7,8-tetrahydro-2-(4'-methyl-β-methylstyrl)naphthalene andtrans-5,8-methano-5,6,7,8-tetrahydro-2-(4'-methylsulphonyl-β-methylstyrl)naphthalene.
 3. A composition suitable for pharmaceutical usecomprising, in a pharmaceutically acceptable carrier, at least onebenzonorbornene derivative of claim
 1. 4. The composition of claim 3 ina form suitable for topical administration, wherein said benzonorbornenederivative is present in an amount ranging from 0.005 to 2 percent byweight of said composition.
 5. The composition of claim 4 wherein saidbenzonorbornene derivative is present in an amount ranging from 0.002 to1 percent by weight of said composition.
 6. The composition of claim 4in the form of an ointment, gel, cream, pomade, powder, tincture,solution, suspension, emulsion, lotion, spray, patch or saturated pad.7. The composition of claim 3 in a form suitable for enteraladministration.
 8. The composition of claim 3 in a form suitable fororal administration.
 9. The composition of claim 3 in the form of asolution or suspension suitable for parenteral administration.
 10. Thecomposition of claim 9 wherein said benzonorbornene derivative ispresent in an amount ranging from 0.01 to 1 mg per ml of said solutionor suspension.
 11. The composition of claim 3 in a form suitable forocular administration.
 12. The composition of claim 3 wherein saidpharmaceutically acceptable carrier is at least one of water, gelatin,lactose, starch, talc, liquid petrolatum, gum arabic, polyalkyleneglycol and magnesium stearate.
 13. The composition of claim 3 which alsoincludes, as an inert or pharmacodynamically active additive, one ormore of a hydrating agent, at antiseborrhoeic agent, an antibiotic, ananti=acne agent, an agent promoting regrowth of hair, ananti-inflammatory agent, a carotenoid, a antipsoriatic agent, anflavoring agent, a preservative, a stabilizer, a moisture-regulatingagent, a pH-regulating agent, an osmotic pressure modifying agent, aUV-A or UV-B screening agent or an antioxidant.
 14. A cosmeticcomposition comprising in a cosmetically acceptable carrier at least onebenzonorbornene derivative of claim
 1. 15. The cosmetic composition ofclaim 14 wherein said benzonorbornene derivative is present in an amountranging from 0.005 to 2 percent by weight of said composition.
 16. Thecosmetic composition of claim 15 wherein said benzonorbornene derivativeis present in an amount ranging from 0.01 to 1 percent by weight of saidcomposition.
 17. The cosmetic composition of claim 14 in the form of alotion, a gel, a cream, a soap or a shampoo.
 18. The cosmeticcomposition of claim 14 which also includes as an inert or cosmeticallyactive additive, one or more of a hydrating agent, an antiseborrheicagent, an antibiotic, an anti-acne agent, an agent promoting growth ofhair, an anti-inflammatory agent, a carotenoid, an antipsoriatic agent,a flavoring agent, a preservative, a stabilizer, a moisture-regulatingagent, a pH-regulating agent, an osmotic pressure modifying agent or anantioxidant.
 19. A method for the treatment of a dermatologicalcomplaint connected with a keratinization(differentiation-proliferation) disorder, of dermatological or othercomplaints with an inflammatory and/or immuno-allergic component, ofbenign or malignant dermatological proliferations, of rheumatoidpsoriasis or of ophthalmological complaints, which comprisesadministering to a subject suffering therefrom or liable thereto aneffective amount of the benzonorbornene derivative of claim
 1. 20. Themethod of claim 19 wherein from 2 mg to 2 g of said derivative isadministered per day per kg of body weight.
 21. The benzonorbornene ofclaim 1, which istrans-5,8-methano-5,6,7,8-tetrahydro-2-(β-methylstyryl) naphthalene.